Project Summary: We are conducting an ongoing study comparing the effects of 10 weeks of fructose or glucose consumption at 25% of energy requirements on lipid parameters and indices of insulin resistance and inflammation in older (+40 years), overweight/obese (BMI: 25-35 kg/m2) adults. Current results from this study provide evidence that consumption of fructose promotes the development of an atherogenic lipid profile and glucose intolerance/insulin resistance within 2 weeks, while glucose consumption does not. Thus, it is likely that diets high in fructose could contribute to the development of metabolic syndrome and cardiovascular disease. We propose to expand our investigation by pursuing the following Specific Aims: 1: Determine the amount of dietary fructose required to produce lipid dysregulation and insulin resistance in younger, normal weight and overweight/obese adults (18-40 years). We propose to conduct a dose-response study in which subjects consume self-selected, ad libitum diets for 2 weeks supplemented with 10, 17.5 or 25% of energy requirements as fructose-sweetened beverages. 2: Compare the effects of consuming two weeks self- selected ad libitum diets containing 10, 17.5 or 25% of energy requirements as high fructose corn syrup (HFCS)-sweetened beverages to the effects induced by fructose in normal weight and overweight/obese adults (18-40 years). We have preliminary data demonstrating that consumption of HFCS- sweetened beverages at 25% of energy requirements, despite containing 45% less fructose than pure fructose, increases postprandial triglycerides to the same degree as consuming 25% energy as pure fructose. Therefore, we hypothesize that HFCS will promote the development of an atherogenic lipid profile comparably to fructose alone. 3: Test the hypothesis that fructose and HFCS will cause comparable increases in ectopic hepatic triglyceride accumulation and insulin resistance. We propose that induction of insulin resistance resulting from fructose consumption is mediated through a mechanism that involves fructose- induced lipid dysregulation and increased ectopic lipid deposition in the liver, rather than a mechanism involving more direct effects of hepatic fructose metabolism. The study is designed as a prospective, blinded diet intervention study, with a 3-day baseline period on a complex carbohydrate diet and a 2-week diet intervention phase, during which the participants consume either fructose- or HFCS -sweetened beverages (providing 10%, 17.5% or 25% of energy) with meal. During the intervention, the subjects reside at home and are provided with fructose- or HFCS-sweetened beverages that are consumed along with a self-selected ad libitum (usual) diet. Procedures, which include 4-hour oral glucose tolerance and deuterated glucose disposal tests, measurement of hepatic triglyceride accumulation by MRI, and 24-hour blood collections are performed during the baseline period and at the end of Intervention Weeks 1 and 2 at the UC Davis Clinical & Translational Science Center Clinical Research Center. Project Narrative: Recent results from our laboratory indicate that drinking beverages sweetened with fructose at 25% of caloric requirements at each meal for 2 weeks causes increased cholesterol and triglyceride levels in the blood and increased insulin resistance in overweight and obese men and women over 40 years old. These changes are associated with an increased risk for heart disease and diabetes, and since consumption of sugar-sweetened beverages containing fructose has more than doubled between 1977 and 2001, these findings have important public health implications. The proposed studies are needed to determine the effects of drinking beverages sweetened with fructose and high fructose corn syrup in younger, normal weight and overweight adults, and to determine the amount of fructose intake that is required to produce these undesirable effects so that safe levels of sugar consumption can be established.